Methods of treating circadian rhythm disorders

ABSTRACT

A method for treating circadian rhythm disorders is described. The method involves the administration of melatonin from about 6 hours to about 19 hours prior to when the normal sleep phase should begin, depending on whether a phase advance shift in circadian rhythms or a phase delay shift is desired. This is typically from about 4 hours to about 17 hours prior to the time of endogenous melatonin onset.

This invention was made with government support under MH 40161 and MH00703 awarded by the National Institutes of Health. The government hascertain rights in the invention.

This is a continuation of application Ser. No. 08/077,426, filed Jun.15, 1993, now U.S. Pat. No. 5,420,152, issued May 30, 1995, which is adivisional of Ser. No. 07/842,723, filed Feb. 25, 1992, now U.S. Pat.No. 5,242,941, issued Sep. 7, 1993, which is a continuation of Ser. No.07/621,866, filed Dec. 4, 1990, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The field of the invention disclosed in this application relates to theregulation of circadian rhythms in humans, and to the synchronization ofcircadian rhythms with the external environment. Specifically, thisinvention describes a method to achieve a chronobiologic (circadianrhythm phase-shifting) effect in humans. In particular, this inventionrelates to the reestablishment of synchrony between a human's endogenousbiological circadian rhythm and the external environment (including thesleep-wake cycle) after its disruption in any of a number of ways. Theinvention further describes a method to specifically advance or delaythe onset of a specific circadian rhythm in a human.

2. Background of the Related Art

The phenomenon of circadian rhythms in biology is well known, andcircadian rhythms are exhibited by all eukaryotic plants and animals,including man. Biological rhythms are periodic fluctuations inbiological properties over time; these include circadian as well asseasonal variations. Circadian, or approximately 24-hour, rhythmsinclude the production of biological molecules such as hormones, theregulation of body temperature, and behaviors such as wakefulness, sleepand periods of activity. In nature, circadian rhythms are closely tiedto environmental cues that impose a 24 hour pattern on many of thesefluctuations. Experimental inquiry has established that when these cuesare absent, most circadian rhythms have a periodicity of approximately25 hours. Circadian rhythms that are not regulated by environmental cuesare said to be free-running. The regulation of circadian rhythms bysignals from the environment is said to involve entrainment of thecircadian rhythms. The environmental signals that effect entrainmenthave been termed zeitgebers, an example of which is the light-darkcycle.

It is thought in the art that the control of circadian rhythms inmammals is mediated by a portion of the brain called the superchiasmaticnuclei (SCN). One of the major circadian rhythms, the pattern ofwakefulness and sleep, is mediated by a feedback loop involving theretina, the SCN and the pineal gland. The pineal gland is primarilyresponsible for the production of melatonin, orN-acetyl-5-methoxytryptamine. Melatonin is believed to be thephysiological mediator of sleep and wakefulness in mammals.

The disruption of circadian rhythms can result in a number ofpathophysiological states in humans; the most common of these is jetlag. The use of melatonin to ameliorate the effects of jet lag has beendescribed in the prior art.

U.S. Pat. Nos. 4,665,086 and 4,600,723 teach the use of melatonin toalleviate the symptoms of jet lag. These patents teach the use of 1-10mg of melatonin, taken at destination bedtime, and again upon prematureawakening in the middle of the night. A number of examples are disclosedin these patents, all of which involve travelers who take these doses ofmelatonin at destination bedtime and report the alleviation of thesymptoms of jet lag.

Without wishing to be bound to this hypothesis, the present inventorsbelieve that U.S. Pat. Nos. 4,665,086 and 4,600,723 are mistaken whenthey describe their use of exogenous melatonin as resulting inrestoration of a circadian rhythm. Rather, the administration ofexogenous melatonin taught by these patents should merely reinforce the(usual) rise in endogenous melatonin which occurs near the time of sleeponset. It is known that melatonin in high doses increases tiredness andthe tendency to sleep (see Arendt et al. Neurosci. Lett. 45: 317-325,1984; Arendt et al. CIBA Found. Syrup. 117: 266-283, 1986). The presentinventors believe that the effect described in U.S. Pat. Nos. 4,665,086and 4,600,723 arises mainly from the soporific, hypnotic andsleep-inducing properties of melatonin administered at high doses, andthat following the teachings of these patents would result in little, ifany, change in the circadian rhythms of endogenous melatonin production.

Arendt et al. Ergonomics 30: 1379-1393 (1987) disclose theadministration of melatonin to alleviate jet lag. Exogenous melatonin isadministered orally from 4 to 6 hours prior to the human's normalbedtime and taken upon awakening in the middle of the night. Thisschedule of melatonin administration was reported subjectively both toimprove sleep quality and decrease sleep latency and to promote a morerapid reestablishment of the circadian rhythms of endogenous melatoninproduction. The present inventors believe that the data presented do notsupport the latter conclusion. No prior art references known to thepresent inventors teach melatonin administration more than 6 hours priorto the patient's normal bedtime to alleviate jet lag in a human. Noprior art references known to the present inventors relate exogenousmelatonin administration to the time interval between suchadministration and the time of endogenous melatonin onset in humans.

Armstrong et al. Experientia 45: 932-938 (1989) disclose that in ratsthe effects of exogenous melatonin administration on the circadianrhythm of the sleep/wake cycle depends on the time of administrationrelative to the sleep/wake cycle, and that the effect was greatest whenexogenous melatonin was administered several hours before the effectivestart of the nocturnal activity cycle. However, these authors wereunable to demonstrate phase-delay shifts or a phase-response curve(PRC); that is, they did not relate the timing of exogenous melatoninadministration to the time of the endogenous melatonin onset.

Gwinner and Benzinger J. Comp. Physiol. 126: 123-129 (1978) teach thatdaily injections of melatonin can entrain the activity/rest cycle inbirds.

Underwood J. Pineal Res. 3: 187-196 (1986) disclosed a PRC for melatoninin the lizard Sceloporus occidentalis.

Mallo et al. Acta Endocrinol. 119: 474-480 (1988) teach theadminstration of 8 mg of melatonin to humans, one hour before bedtimeover a course of four days, results in a slight phase advance three daysafter cessation of the melatonin treatment.

Entrainment and regulation of the melatonin circadian rhythm has thusbeen demonstrated in a number of animal species. The present inventorsare the first to disclose a PRC for melatonin in a human, and perhaps inany mammalian species. The ability to effect an actual change in phaseof the circadian rhythm would be useful for the alleviation of a numberof circadian rhythm related disorders, as will be further discussed inthe embodiments below. This application discloses a method to advance ordelay the onset of the production of endogenous melatonin, and henceactually affect the regulation of an endogenous circadian rhythm in man.

SUMMARY OF THE INVENTION

This invention relates to a method for achieving a chronobiologic(phase-shifting) effect in a human. This effect is achieved byregulation of a human's circadian rhythm. Specifically, the circadianphase-shifting effect is achieved by the administration of exogenousmelatonin, which naturally occurs in the human only during the night.The timing of the nighttime onset of melatonin production in aparticular individual may be expected to vary from person to person. Thecircadian rhythm of melatonin production in a human is entrainedprincipally by the (bright) light-dark cycle and reflects a variety ofother biological properties which vary with a circadian rhythm. Themethod of the invention entails the phase-shifting of the circadianrhythm by administration of exogenous melatonin. More specifically, themethod of the invention involves the administration of a particulardosage of melatonin to the human. The particular dosage is lower thandosages taught by others, and is designed to achieve melatonin levelswhich are substantially equal to physiological levels in the human.Further, the method of the invention relates to the timing of theadministration of the dosage of melatonin to the human. The timing ofthis dosage in the human is described to specifically phase-shift thecircadian rhythm of endogenous melatonin production. The methoddescribed in the invention can be used to advance or delay the phase ofthe circadian rhythm of melatonin production in the human. In this way,the present invention is able to alleviate jet lag and other circadianrhythm disorders of both the phase-delay and the phase-advance types.

The present inventors have discovered that the time of administration ofexogenous melatonin relative to the time of endogenous melatonin onsetis critical to the production of the appropriate phase-shifting effect.The time of administration of exogenous melatonin must be carefully setrelative to the time of endogenous melatonin onset, preferably from morethan 4 hours to about 8 hours before endogenous melatonin onset when aphase advance is desired, and about 9 hours to about 17 hours beforeendogenous melatonin onset when a phase-delay is desired. Since theendogenous melatonin onset typically occurs about 2 hours prior to whenthe normal sleep phase should begin, exogenous melatonin should bepreferably administered from more than 6 hours to about 10 hours priorto the commencement of the patient's normal sleep phase when aphase-advance is desired, and about 11 hours to about 19 hours prior tothe commencement of the patient's normal sleep phase when a phase-delayis desired. The preferred time of administration of exogenous melatoninfor a particular individual human will be unique, depending on theindividual's time of endogenous melatonin onset, which can vary markedlyfrom individual to individual (between 7 PM to 11 PM for mostindividuals). An increase of at least 15-30 minutes of phase shiftingwill occur for each day of exogenous melatonin treatment administered asdescribed in a preferred embodiment below.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 discloses the experimental results of Example 2;

FIG. 2 discloses the experimental results of Example 3;

FIGS. 3 and 4 disclose the experimental results of Example 4; and

FIGS. 5 and 6 disclose the experimental results of Example 5.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The amount of melatonin administered to the human patient should besufficient to achieve the desired circadian phase-shifting effect. In apreferred embodiment of this invention, a dosage of about 0.25 mg toabout 0.75 mg, most preferably about 0.50 mg, of exogenous melatonin isused to effect the desired change in phase of the circadian rhythms ofendogenous melatonin production. In a preferred embodiment, the totaldose of melatonin is given in two or more smaller portions to the humanpatient over an interval of about two hours if the person is awake. Onedose time is preferred if the person is asleep.

Pharmaceutical quality melatonin is commercially available. The dosageof melatonin may be administered orally, by injection, via a transdermalpatch or by implantation of a reservoir designed to release a steadydosage of melatonin over time. In a preferred embodiment of thisinvention, melatonin is administered orally.

In a preferred embodiment of this invention, a phase advance in thecircadian rhythm rhythms of endogenous melatonin production is effectedby the administration of an amount of exogenous melatonin sufficient toachieve the phase advance from more than 6 hours to about 10 hours,preferably from about 7 to about 10 hours, most preferably about 8hours, before the human's normal sleep phase should begin. This istypically from about 4 hours to about 8 hours, most preferably about 6hours, before the patient's endogenous melatonin onset.

A phase delay in the circadian rhythm of endogenous melatonin productionis effected by the administration of an amount of exogenous melatoninsufficient to achieve the phase delay from about 11 to about 19 hours,most preferably from about 12 to about 16 hours, prior to when thehuman's normal sleep phase should begin. This is typically from about 9hours to about 17 hours, most preferably from about 10 to about 14hours, before the patient's endogenous melatonin onset.

A modification of the method of Lewy and Markey (Science 201: 741-3,1978) may be used to determine the time of onset of the patient'sendogenous melatonin production. The preferred use of this method istaught in Example 1.

The present invention may be used in, but is not limited to, thefollowing situations to achieve chronobiologic effects and/or toalleviate circadian rhythm disorders: jet lag; shift work; astronauts inorbit around the Earth, on missions in space to the Earth's moon or tothe planets or out of the known solar system, or in training for suchmissions; submariners, or persons confined for research, exploration orindustrial purposes below the seas; miners, explorers, spelunkers,researchers or those confined beneath the Earth; psychiatric patients;insomniacs; the comatose, or those who need to be maintained in a stateof unconsciousness for medical, psychiatric or other reasons; medicalresidents, nurses, firemen, policemen or all those whose duties requirealertness and wakefulness at evening or nighttime hours, or thosedeprived of sleep for various periods because of their duties orresponsibilities; the infantry, or other members of the armed forceswhose duties require extreme levels of alertness and wakefulness, andwho may be sleep deprived in the performance of these duties; the blindor sight-impaired, or all those whose ability to distinguish differencesin light and dark may be permanently or temporarily impaired; residentsof the far North or Antarctica, or all those who live in a climate orclimates that possess abnormal amounts of light or darkness; thosesuffering from seasonal affective disorder, or other forms ofdepression; the aged; the sick, or all those who require dosages ofmedication at appropriate times in the circadian cycle; and animalbreeders, for use in controlling circadian time.

The following examples describe certain specific embodiments of theinvention. However, many additional embodiments not described hereinnevertheless fail within the spirit and scope of the present inventionand claims.

EXAMPLE 1 Detection of Melatonin Levels in Human Plasma

Prior to collection of human blood, subjects are kept in dim light forabout 5 hours (usually between 6 PM and 11 PM). An intravenous line orheparin lock is inserted in a forearm vein and 5 ml of blood drawn every30 minutes between 7 PM and 11 PM. The blood samples are centrifuged for5 minutes at 1000 g and 4° C., and the plasma aspirated into a silanizedglass or plastic tube. Samples are assayed immediately or frozen forlater analysis. To a 1 ml aliquot of such plasma was added 15-40picograms of N-acetyl-5-methoxy(α,α,β,β-D₄)tryptamine as achromatographic control. An equal volume of normal saline is added andthe mixture gently shaken With 10 volumes of petroleum ether. Theorganic phase is removed, and melatonin and the addedN-acetyl-5-methoxy(α,α,β,β-D₄)tryptamine control extracted from theaqueous phase with 10 volumes of chloroform. The aqueous phase is thendiscarded, and the chloroform evaporated to dryness.

The dried extract containing melatonin and the addedN-acetyl-5-methoxy(α,α,β,β-D₄)tryptamine control is dissolved in 0.4 mlof anhydrous acetonitrile. The melatonin and the addedN-acetyl-5-methoxy(α,α,β,β-D₄)tryptamine control are then derivatized bythe addition of 25 μl of pentafluoroproprionic acid anhydride and 0.5 mlof a solution of 5% trimethylamine in anhydrous benzene and reacted at100° C. for 10 minutes. The reaction products are washed sequentiallywith 1 ml water and 1 ml 5% ammonium hydroxide. The mixture iscentrifuged briefly at 13,000 g and the organic phase withdrawn andevaporated to dryness under nitrogen. The dried extract is partitionedbetween 0.5 ml acetonitrile and 1 ml hexane by vigorous mixing followedby centrifugation. The hexane layer is removed and the acetonitrileevaporated to dryness under nitrogen. This partitioning step isperformed two times for each sample. The dried extract is re-patitionedfor storage. The derivatives are stable and can be stored at -20° C. forseveral weeks.

The amount of melatonin present in each sample is determined by analysisusing a gas chromatograph-mass spectrometer (GC-MS). Before injectiononto the GC column, the dried derivatives are dissolved in 15 μl ofethyl acetate. Approximately half this volume was applied to a 30 m×25μm fused silica capillary column (0.15 micron film thickness with a 1mretention gap (DB-225, J & W Scientific, Folsom, Calif.)). The oven isprogrammed from 60° C. to 240° C. (at 25.5° C./min) with helium ascarrier gas (10 psi head pressure) and methane used as make-up gas(ionizer, 0.6 torr). Derivatized melatonin and the addedN-acetyl-5-methoxy(α,α,ββ-D₄)tryptamine derivatized control are found toelute from the column after 10-14 minutes. Mass spectrographic analysisof the column eluate is then performed. Mass spectra are recorded usinga Finnigan 4000-GC-CI analyzer and INCOS data system. A Finnigan PPIMCIelectron multiplier with 3 kV conversion was used, signal referenced toground. The relative signals of melatonin and the addedN-acetyl-5-methoxy(α,α,β,β-D₄)tryptamine control are detected at m/c(mass/charge) ratios of 320 and 323, respectively. The amount ofmelatonin present in any unknown sample can be determined by comparisonof the ratio of the intensities of these signals to a standard curve,prepared as described using known amounts of melatonin and addedN-acetyl-5-methoxy(α,α,β,β-D₄)tryptamine control.

EXAMPLE 2

Without light perception, blind people often have circadian rhythms thatfree run with a period greater than 24 hours. We have been successful inphase-shifting a free running circadian rhythm in at least one blindsubject by administering 0.5 mg doses of melatonin orally.

A blind subject whose circadian rhythms were free-running was placed ona three-week regimen to phase-shift his circadian rhythms usingadministration of exogenous melatonin. The subject was given 0.25 mg ofmelatonin orally at 1900 and 2100 hours (clock time) every day for threeweeks. The effect of exogenous melatonin administration on the time ofendogenous melatonin onset is disclosed in FIG. 1. The cumulative phaseadvance seen in this subject is equivalent to the phase advance obtainedwhen a much higher dose (5 mg) was used. These results confirm thatexogenous melatonin administration can effect a phase advance in ahuman.

EXAMPLE 3

The effect of exogenous melatonin administration on circadian rhythm ofsighted people was tested. Eight normal subjects were treated in atwo-week protocol, similar to the one used in Example 2. During thefirst week, the subjects were given a placebo at 1700 and 1900 hours andthe time, extent and amount of dim light melatonin onset (DLMO) wasmeasured as described in Example 1. During the second week, subjectswere given placebo at 1700 and 1900 hours for two days, and thenmelatonin was administered in two doses of 0.25 mg at 1700 and 1900hours for 4 days and the subjects' DLMO determined.

Seventeen trials were conducted on the eight subjects. The results ofthis study are shown in FIG. 2. The Figure shows the relationshipbetween the degree of phase shift obtained and the interval between thetime of administration of exogenous melatonin and the endogenous DLMO.This interval is also known as the phase angle difference. The earlierthe exogenous melatonin is administered the greater is the magnitude ofthe phase advance; that is, there is a positive correlation between theextent of phase advance achieved by exogenous melatonin administrationand the time interval between the time of exogenous melatoninadministration and the time of endogenous melatonin onset. These resultsconfirm that exogenous melatonin administration can effect a phaseadvance in humans, and that the timing of exogenous melatoninadministration relative to the onset of endogenous melatonin iscritically important for phase shifting circadian rhythms.

EXAMPLE 4

The effect of exogenous melatonin treatment administered at earliertimes relative to the endogenous melatonin rhythm was tested in sightedpeople. Twenty-four trials were conducted in the eight normal subjectswho were treated in a two-week protocol similar to the one used inExample 3. During the first week, placebo was administered and the time,extent and amount of dim light melatonin onset (DLMO) was determined.Subsequently in the second week, melatonin was administered at varioustimes prior to the time of endogenous melatonin onset, and the subjects'endogenous melatonin onset was determined. The results of this study areshown in FIGS. 3 and 4. FIG. 3 expresses the results in terms ofcircadian time (assuming the DLMO occurs at (CT) 14), and FIG. 4expresses the same results in terms of military time (assuming that DLMOis at 2000 hours (8 PM)). These results show that the maximum degree ofphase advance in the onset of endogenous melatonin occurred afteradministration of exogenous melatonin at circadian time (CT) 8, or 6hours prior to the normal time of melatonin onset in the subjects (CT14). This corresponds to a time of about 8-10 hours before normalbedtime in these subjects. The observed phase advance declines rapidlywhen exogenous melatonin is administered prior to CT 8. Between CT 8 andCT 14, the decline in the degree of phase advance is linear andproportional to the phase angle between time of administration and timeof endogenous onset. Minimal effect, if any, on the circadian rhythm ofendogenous melatonin onset is seen when the time of administration ofexogenous melatonin coincides with the normal time of onset ofendogenous melatonin (CT 14).

EXAMPLE 5

Experiments to investigate the use of exogenous melatonin to effect aphase delay were also performed. These experiments followed the protocolexplained in Example 4; however, the time of administration of melatoninwas altered. A total of 30 rials using nine subjects were performed. Theresults of this experiment are shown in FIGS. 5 and 6. In this regime,exogenous melatonin was administered about 11-19 hours before normalbedtime. It was found that administration of exogenous melatonin fromabout 9 hours to about 17 hours before the endogenous melatonin onsetresulted in the greatest degree of phase delay in the onset ofendogenous melatonin production.

EXAMPLE 6

Pre-mature, immature and mature infants typically experience at least aperiod characterized by erratic sleep schedules, including sleepingduring the day and not sleeping at night. These characteristics areconsistent with these infants having a free-running circadian rhythm ofsleep and wakefulness, which free-running circadian rhythms may beentrained to a 24-hour pattern of sleep and wakefulness by theadministration of exogenous melatonin.

In order to entrain infants having a free-running circadian rhythm whichplaces their pattern of sleep and wakefulness out of synchrony withtheir external environment (defined herein as including the sleep/wakepattern of the infant's parents), an optimal dose of less than about 1mg of melatonin is administered to an infant at about 2 o'clock p.m.According to the melatonin PRC disclosed herein, a phase advance isoptimally elicited by administration of melatonin at circadian time (CT)7. Administration of exogenous melatonin at about 2 P.M. in an infantwith a free-running circadian rhythm of sleep and wakefulness willtypically result in the infant becoming sleepy at a time no later thannine hours after administration, or at about 11 P.M.

Melatonin can be administered as disclosed hereinabove for adultadministration (e.g., transdermally, orally, or by injection). However,melatonin is most advantageously administered to an infant in milk,including in breast milk obtained from the infant's mother. This isparticularly important for mothers who extract a portion of their milkduring the day for feeding their infants at night; due to the mother'smelatonin production, this milk is almost completely melatonin-free, andthus is sub-optimal for entraining the sleep/wake cycle in an infant.Breast milk and milk from other sources, and infant formulae, may besupplemented with melatonin to a total dose of about 1 mg foradministration to infants to achieve a circadian rhythm phase shift.

In addition, exogenous melatonin administration may promote sleepinessin infants when administered later than 2 P.M., and one consequence ofinduced sleepiness at a desired time is to induce a circadian rhythmphase shift via the shifted light/dark cycle and so entrain the infant'sendogenous circadian rhythms to the desired sleep and wake times. Onecaveat for melatonin administration at times earlier or much later than2 P.M. is that administration at times appropriate for inducing a phasedelay, using the teachings of the melatonin PRC herein, should beavoided. Preferably, exogenous melatonin may be administered at aninfant's bedtime (or slightly later) to promote sleep and to avoidinduced opposite phase shifts on the infant's circadian rhythms betweenthis and the earlier (i.e., 2 P.M.) adminstration of exogenousmelatonin.

We claim:
 1. A method for achieving a phase-shifting effect in a humanhaving a free-running circadian rhythm that is out of synchrony with theexternal environment, the method comprising administering melatonin tothe human at a time prior to an individual human's endogenous melatoninonset time, the amount of melatonin administered being sufficient toachieve a phase-shifting effect in the human, said amount being lessthan 1 mg.
 2. The method of claim 1 wherein the human is blind.
 3. Themethod of claim 1 wherein human is an infant.
 4. The method of claims 1,2 or 3 wherein the phase-shifting effect is a phase advance andmelatonin is administered at about 4 hours to about 8 hours prior to thehuman's endogenous melatonin onset time.
 5. The method of claim 4wherein melatonin is administered at about 6 hours prior to the human'sendogenous melatonin onset time.
 6. The method of claim 4 whereinmelatonin is administered at about circadian time (CT)
 8. 7. The methodof claim 4 wherein melatonin is administered at about 8 hours prior tothe human's desired sleep onset time.
 8. The method of claim 4 whereinmelatonin is administered at about 8 hours after the human's sleepoffset time.
 9. The method of claims 1, 2 or 3 wherein thephase-shifting effect is a phase delay and melatonin is administered atabout 12 hours to about 16 hours prior to the human's endogenousmelatonin onset time.
 10. The method of claim 9 wherein melatonin isadministered at about 14 hours prior to the human's endogenous melatoninonset time.
 11. The method of claim 9 wherein melatonin is administeredat about circadian time (CT)
 0. 12. The method of claim 9 whereinmelatonin is administered at about 16 hours prior to the human's desiredsleep onset time.
 13. The method of claim 9 wherein melatonin isadministered at the human's sleep offset time.
 14. The method of claim1, wherein melatonin is administered in a multiplicity of doses andadministered at different times, wherein the total administered dose isless than about 1 mg, and the dose is administered over a period ofabout 1 to about 4 hours.
 15. The method of claim 14, wherein melatoninis administered in two equal doses.
 16. The method of claim 15, whereinthe melatonin administration times are separated by less than about 1hour.
 17. The method of claim 15, wherein the earlier of the melatoninadministration times is about 8 hours prior to the human's desired sleeponset time.
 18. The method of claim 15, wherein the earlier of themelatonin administration times is about 8 hours after the human's sleepoffset time.
 19. The method of claim 15, whereto the earlier of themelatonin administration times is about 16 hours prior to the human'sdesired sleep onset time.
 20. The method of claim 15, wherein theearlier of the melatonin administration times is about the human's sleepoffset time.
 21. The method of claims 1, 2 or 3, wherein the circadianrhythm phase-shifting effect results in the human's circadian rhythm ofsleep and wakefulness having a period of about 24 hours.
 22. The methodof claims 1, 2 or 3, wherein the circadian rhythm phase-shifting effectresults in a partial entrainment of the human's circadian rhythm ofsleep and wakefulness, thereby increasing the proportion of time thatsaid circadian rhythm has a period of about 24 hours.
 23. A method forachieving a phase-shifting effect in a human infant comprising thefollowing steps:a) determining the time of the infant's endogenousmelatonin onset; and b) administering an amount of melatonin to theinfant in milk at a specific time prior to the infant's endogenousmelatonin onset, the amount of melatonin being sufficient to achieve thephase-shifting effect in the infant, said amount being less than 1 mg.24. The method of claim 23 wherein the phase-shifting effect is a phaseadvance and the melatonin is administered at about 4 hours to about 8hours prior to the infant's endogenous melatonin onset.
 25. The methodof claim 23 wherein the phase-shifting effect is a phase delay and themelatonin is administered at about 9 hours to about 12 hours prior tothe infant's endogenous melatonin onset.
 26. A method for achieving aphase-shifting effect in a blind human comprising the following steps:a)determining the time of the blind human's endogenous melatonin onset;and b) administering an amount of melatonin to the blind human at aspecific time each day prior to the blind human's endogenous melatoninonset, the amount of melatonin being sufficient to achieve thephase-shifting effect in the human, said amount being less than 1 mg.27. The method of 26 wherein the phase-shifting effect is a phaseadvance and the melatonin is administered at about 4 hours to about 8hours prior to the human's endogenous melatonin onset.
 28. The method ofclaim 26 wherein the phase-shifting effect is a phase delay and themelatonin is administered at about 6 hours to about 19 hours prior tothe human's endogenous melatonin onset.